CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.
Cell
; 157(3): 651-63, 2014 Apr 24.
Article
en En
| MEDLINE
| ID: mdl-24766810
ABSTRACT
Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fosfotransferasas
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Factores de Transcripción
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ARN de Transferencia
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Proteínas Nucleares
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Cerebelo
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Empalme del ARN
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Proteínas de Pez Cebra
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Factor de Especificidad de Desdoblamiento y Poliadenilación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cell
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos